The present invention is directed to processes for making ondansetron and intermediates thereof involving a water binding agent.
Ondansetron is a pharmaceutically active agent commonly used for the treatment of nausea and vomiting, particularly when associated with cancer chemotherapy treatments. In marketed compositions (sold under brand name ZOFRAN® by Glaxo), ondansetron is used as a free base in rapidly dissolvable tablets and as a hydrochloride salt in injections, tablets for oral administration and oral solutions. Ondansetron is chemically named 1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1H-imidazol-1yl)methyl-4H-carbazol-4-one and has the following chemical structure:
Because the ondansetron molecule has one optically active carbon, it can exist as two different enantiomers or as a mixture thereof, i.e., as a racemate. Both enantiomers are pharmaceutically active, however only the racemate is marketed thus far.
DE 3502508 and corresponding U.S. Pat. No. 4,695,578 describe ondansetron and various other 3-imidazole-tetrahydrocarbazolones, as useful in the treatment of migraine and psychotic disorders such as schizophrenia. These patents disclose several synthetic routes for making ondansetron. One example uses a transamination reaction as shown below:
wherein an aqueous solution of 3-((dimethylamino)methyl)-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride is treated with 2-methylimidazole and heated at reflux for twenty hours. The crude ondansetron product was then recrystallized from methanol. It is not fully clear whether the transamination is a direct nucleophilic substitution or if it proceeds by an elimination-addition mechanism, i.e. via an exocyclic methylene compound, shown below, that is formed by elimination of the amine moiety.

However, no example is given for making the 3-dimethylamino-9-methyl-carbazolone starting material used therein. The synthesis of an analogous 3-dimethylamino-9-phenyl-carbazolone is shown as the only example given of how to make a 3-dimethylamino substituted starting compound. In this example, a solution of 1,2,3,9-tetrahydro-9-phenyl-4Hcarbazol-4-one, dimethylamine hydrochloride and paraformaldehyde are stirred in glacial acetic acid under reflux for forty-two (42) hours and then allowed to cool. After concentrating in vacuo, a residual brown gum was stirred with water, ethyl acetate and brine. The resulting solid was filtered off, washed and dried.
Chinese patents CN 1107474 and CN 1110970 describe the synthesis of ondansetron by reacting an N-methyltetrahydrocarbazol-4-one with paraformaldehyde, 2-methylimidazole and dimethylamine or diethylamine hydrochloride in acetic acid. Reaction times are 20–30 hours and the reported yields are rather poor.
CN 1105994 describes the same reaction, however performed in inert solvent under presence of acidic ion-exchange resin. The reaction temperatures are 50–140° C. and reaction times are 80–200 hours.
While the formation of ondansetron by a transamination reaction with 2-methylimidazole is known, it would be desirable to improve the reaction time and/or yield, especially for commercial scale production of ondansetron.